1. Field of the Invention
The present invention relates to certain compounds and to methods for the preparation and the use of certain compounds in the fields of chemistry and medicine. More specifically, the present invention relates to compounds and procedures for making and using compounds that are useful as antimicrobial agents, and relates to pharmaceutical dosage forms comprising such compounds.
2. Description of the Related Art
Antimicrobials are generally used to destroy or suppress the growth or reproduction of microbes such as bacteria. Antimicrobial compounds may act on the targeted microbes in a variety of ways. For example, the antimicrobial compound may prevent DNA or protein synthesis, may alter the cell wall of a microbe, either by altering cell wall permeability or by altering cell wall synthesis and repair.
While there are numerous known antimicrobial compounds, and numerous known mechanisms by which antimicrobial compounds may function, concerns over the availability of antibiotic treatment options, for both early- and late-stage infections from bacteria, have recently increased. There are many reasons for the increase in concern, but one major reason relates to the potential of bioweapons engineering of resistant isolates, and evolutionary development of resistance to existing antibiotics. As such, new antimicrobials and new sources of antimicrobials are desired and are increasingly valuable.
There are many characteristics that can be relevant when trying to decide whether or not a particular compound is useful as an antimicrobial. Relevant factors include, but are not limited to, the relative potency of the compound against a specific microbe or against a spectrum of microbes, and the relative selectivity of the antimicrobial activity of the compound in targeting the invading pathogen versus the host organism. There are also long-term concerns, including the likelihood that the microbe may develop resistance to one or more antimicrobial compound. There are also practical concerns, such as the cost and commercial availability of the antimicrobial compound.
A possible source of antimicrobial compounds is marine-derived natural products. The oceans are massively complex and house a diverse assemblage of microbes that occur in environments of extreme variations in pressure, salinity, and temperature. Marine microorganisms have developed unique metabolic and physiological capabilities that not only ensure survival in extreme habitats, but also offer the potential to produce metabolites that would not be observed from terrestrial microorganisms. (Okami, Y. 1993 J Mar Biotechnol 1:59.) Representative structural classes of such metabolites include terpenes, peptides, polyketides, and compounds with mixed biosynthetic origins. Many of these molecules exhibit anti-tumor, anti-bacterial, anti-fungal, anti-inflammatory or immunosuppressive activities (Bull, A. T. et al. 2000 Microbiol Mol Biol Rev 64:573; Cragg, G. M. & D. J. Newman 2002 Trends Pharmacol Sci 23:404; Kerr, R. G. & S. S. Kerr 1999 Exp Opin Ther Patents 9:1207; Moore, B. S 1999 Nat Prod Rep 16:653; Faulkner, D. J. 2001 Nat Prod Rep 18:1; Mayer, A. M. & V. K. Lehmann 2001 Anticancer Res 21:2489), validating the utility of this source for isolating therapeutic agents. Further, the isolation of novel antibiotics that represent alternative mechanistic classes to those currently on the market will likely address mechanism-based resistance that may have been engineered into pathogens for bioterrorism purposes.
One such class of compounds, studied in other, unrelated, fields of research, is the bis-indole pyrrole and, in particular, chromopyrrolic acid. A subset of this class of molecules is disclosed by Hoshino et al. (Biosci, Biotech, Biochem, 57, 775–781 (1993)). Hashimoto et al. (Tetrahedron Letters 35:2559–2560 (1994) suggests that one particular derivative, a doubly substituted pyrrole with two methoxy carbonyls attached symmetrically to the pyrrole, had moderate anti-HSV-1 virus activity in vitro. The functionality of this compound, and of its analogs, is not well understood. Other references have examined similar derivatives for these compounds (Frode et al. Tetrahedron Lett. 35:1689–1690 (1994)).
More recently, Sodeoka et al., (U.S. Pat. No. 6,589,977, issued Jul. 8, 2003), which is incorporated by reference herein, has suggested a role for bis-indole pyrrole derivatives as cell death inhibitors. Sodeoka et al. examined several different bis-indole pyrrole derivatives for cell death inhibitory activity.